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Clonal analysis of lineage fate in native haematopoiesis

机译：天然造血系统血统命运的克隆分析

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摘要

Haematopoiesis, the process of mature blood and immune cell production, is functionally organized as a hierarchy, with self-renewing haematopoietic stem cells and multipotent progenitor cells sitting at the very top(1,2). Multiple models have been proposed as to what the earliest lineage choices are in these primitive haematopoietic compartments, the cellular intermediates, and the resulting lineage trees that emerge from them(3-10). Given that the bulk of studies addressing lineage outcomes have been performed in the context of haematopoietic transplantation, current models of lineage branching are more likely to represent roadmaps of lineage potential than native fate. Here we use transposon tagging to clonally trace the fates of progenitors and stem cells in unperturbed haematopoiesis. Our results describe a distinct clonal roadmap in which the megakaryocyte lineage arises largely independently of other haematopoietic fates. Our data, combined with single-cell RNA sequencing, identify a functional hierarchy of unilineage- and oligolineage-producing clones within the multipotent progenitor population. Finally, our results demonstrate that traditionally defined long-term haematopoietic stem cells are a significant source of megakaryocyte-restricted progenitors, suggesting that the megakaryocyte lineage is the predominant native fate of long-term haematopoietic stem cells. Our study provides evidence for a substantially revised roadmap for unperturbed haematopoiesis, and highlights unique properties of multipotent progenitors and haematopoietic stem cells in situ.
机译：造血过程是成熟血液和免疫细胞产生的过程，功能上是按等级组织的，自我更新的造血干细胞和多能祖细胞位于最顶端（1,2）。关于这些原始造血区室，细胞中间体以及由此产生的谱系树，最早的谱系选择提出了多种模型（3-10）。鉴于大多数关于血统结果的研究都是在造血移植的背景下进行的，因此与自然命运相比，目前的血统分支模型更可能代表血统潜力路线图。在这里，我们使用转座子标记来克隆追踪不受干扰的造血过程中祖细胞和干细胞的命运。我们的结果描述了一个独特的克隆路线图，其中巨核细胞谱系在很大程度上独立于其他造血命运。我们的数据与单细胞RNA测序相结合，确定了多能祖细胞群中产生单系和寡系的克隆的功能层次。最后，我们的结果表明，传统上定义的长期造血干细胞是巨核细胞限制性祖细胞的重要来源，这表明巨核细胞谱系是长期造血干细胞的主要天然命运。我们的研究为大幅修订造血功能的路线图提供了证据，并突出了多能祖细胞和造血干细胞的独特特性。

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  • 来源
    《Nature》 |2018年第7687期|212-216|共5页
  • 作者

    Rodriguez-Fraticelli Alejo E.; Wolock Samuel L.; Weinreb Caleb S.; Panero Riccardo; Patel Sachin H.; Jankovic Maja; Sun Jianlong; Calogero Raffaele A.; Klein Allon M.; Camargo Fernando D.;

  • 作者单位

    Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA|Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA;

    Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA;

    Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA;

    Univ Torino, Dept Clin & Biol Sci, Ctr Mol Biotechnol, I-10126 Turin, Italy;

    Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA;

    Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA;

    Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA|Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA|ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;

    Univ Torino, Dept Clin & Biol Sci, Ctr Mol Biotechnol, I-10126 Turin, Italy;

    Harvard Med Sch, Dept Syst Biol, Boston, MA 02115 USA;

    Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA|Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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